Upadacitinib vs Tofacitinib: A Detailed Comparison

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// ═══════════════════════════════════════════════════════════
// SLIDE 1 — TITLE
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  s.addText("A Comprehensive Clinical Review", { x: 0.5, y: 2.4, w: 5.5, h: 0.6, fontSize: 20, color: C.teal, fontFace: "Calibri", margin: 0 });

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// ═══════════════════════════════════════════════════════════
// SLIDE 2 — TABLE OF CONTENTS
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    ["02", "JAK-STAT Signalling Pathway", C.midTeal],
    ["03", "Mechanism of Action", C.midTeal],
    ["04", "Approved Indications", C.teal],
    ["05", "Rheumatoid Arthritis – Efficacy", C.midTeal],
    ["06", "Other Inflammatory Diseases", C.teal],
    ["07", "Dosing & Administration", C.midTeal],
    ["08", "Safety Profile – Overview", C.teal],
    ["09", "ORAL Surveillance & Class Warnings", C.red],
    ["10", "Drug Interactions & Special Populations", C.amber],
    ["11", "Upadacitinib vs Tofacitinib", C.midTeal],
    ["12", "Upadacitinib vs Biologics", C.teal],
    ["13", "Patient Selection", C.midTeal],
    ["14", "Monitoring & Follow-up", C.teal],
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// SLIDE 3 — DRUG OVERVIEW
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    ["Selectivity", "Selective JAK1 inhibitor (>70x selectivity for JAK1 over JAK2 and JAK3)"],
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    ["FDA Approval", "August 2019 (RA); expanded to PsA, AxSpA, AD, UC, Crohn's"],
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    ["Molecular Weight", "380.84 g/mol"],
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// ═══════════════════════════════════════════════════════════
// SLIDE 4 — JAK-STAT PATHWAY
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// ═══════════════════════════════════════════════════════════
// SLIDE 5 — MECHANISM OF ACTION
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    "Binds reversibly to the ATP-binding site of JAK1 kinase domain",
    "Competitively inhibits ATP binding → prevents JAK1 auto-phosphorylation",
    "Blocks downstream STAT protein phosphorylation and nuclear translocation",
    "Suppresses transcription of pro-inflammatory cytokines (IL-6, IL-2, IFN-γ, GM-CSF)",
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// ═══════════════════════════════════════════════════════════
// SLIDE 6 — APPROVED INDICATIONS
// ═══════════════════════════════════════════════════════════
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    { name: "Ankylosing Spondylitis (AS)", dose: "15 mg OD", year: "2022", note: "Active AS, inadequate response to NSAIDs", color: C.navy },
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    { name: "Atopic Dermatitis (AD)", dose: "15 or 30 mg OD", year: "2022", note: "Moderate-to-severe refractory AD ≥12 years (FDA); ≥18 yrs EMA", color: C.amber },
    { name: "Ulcerative Colitis (UC)", dose: "45 mg induction → 30 mg maint.", year: "2023", note: "Moderate-to-severe active UC, inadequate response to prior therapy", color: C.green },
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// ═══════════════════════════════════════════════════════════
// SLIDE 7 — RA EFFICACY
// ═══════════════════════════════════════════════════════════
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      highlight: "Superior to TNF inhibitor",
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    {
      name: "SELECT-MONOTHERAPY",
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      comparator: "UPA monotherapy vs MTX",
      result: "UPA 15 mg monotherapy superior to MTX for ACR20/50/70 at Wk 14; DAS28-CRP <3.2 significantly higher",
      highlight: "Effective as monotherapy",
      color: C.midTeal,
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    {
      name: "SELECT-NEXT",
      population: "csDMARD-IR",
      comparator: "UPA + csDMARD vs placebo",
      result: "Significantly higher ACR20 at Wk 12 (64% vs 36%); rapid onset within 1–2 weeks",
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      color: C.navy,
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    {
      name: "SELECT-CHOICE",
      population: "bDMARD-IR (failed biologics)",
      comparator: "vs Abatacept",
      result: "Higher DAS28-CRP reduction and more remission at Wk 12; but more AEs vs abatacept",
      highlight: "Superior to abatacept",
      color: "#1565C0",
    },
    {
      name: "SELECT-EARLY",
      population: "MTX-naïve patients",
      comparator: "UPA vs MTX",
      result: "UPA 15 mg: higher ACR20/50/70, less radiographic progression vs MTX alone",
      highlight: "MTX-naïve benefit",
      color: C.green,
    },
  ];

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    const h = 2.05;

    card(s, x, y, w, h, C.white);
    s.addShape(pres.shapes.RECTANGLE, { x, y, w, h: 0.28, fill: { color: t.color }, line: { color: t.color } });
    s.addText(t.name, { x, y, w, h: 0.28, fontSize: 9.5, bold: true, color: C.white, align: "center", valign: "middle", fontFace: "Calibri", margin: 0 });
    s.addText(t.population, { x: x + 0.1, y: y + 0.32, w: w - 0.2, h: 0.22, fontSize: 8.5, bold: true, color: C.navy, fontFace: "Calibri", margin: 0 });
    s.addText(t.comparator, { x: x + 0.1, y: y + 0.52, w: w - 0.2, h: 0.2, fontSize: 8, color: C.grey, italic: true, fontFace: "Calibri", margin: 0 });
    s.addText(t.result, { x: x + 0.1, y: y + 0.75, w: w - 0.2, h: 0.85, fontSize: 8, color: C.dark, fontFace: "Calibri", margin: 0 });
    badge(s, t.highlight, x + 0.1, y + h - 0.38, w - 0.2, t.color);
  });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 8 — OTHER INFLAMMATORY DISEASES
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  accentBar(s);
  leftStrip(s);
  slideTitle(s, "Efficacy in Other Inflammatory Diseases");

  const diseases = [
    {
      name: "Psoriatic Arthritis",
      trials: "SELECT-PsA 1 & 2",
      detail: "Both UPA 15 mg and 30 mg noninferior to adalimumab in biologic-naïve PsA patients (1704 pts). Significant improvements in joint counts, enthesitis, dactylitis, and skin PASI.",
      color: C.teal
    },
    {
      name: "Ankylosing Spondylitis / nr-AxSpA",
      trials: "SELECT-AXIS 1 & 2",
      detail: "Significantly higher ASAS40 response vs placebo at Wk 14. Effective in both bDMARD-naïve and TNFi-IR patients.",
      color: C.midTeal
    },
    {
      name: "Atopic Dermatitis",
      trials: "Measure Up 1 & 2, AD Up",
      detail: "65–75% of patients achieving EASI-75 at Wk 16. Head-to-head vs dupilumab: UPA 30 mg showed superior EASI-75 and IGA response in some studies.",
      color: C.amber
    },
    {
      name: "Ulcerative Colitis",
      trials: "U-ACHIEVE, U-ACCOMPLISH",
      detail: "Induction: 45 mg for 8 weeks → remission. Maintenance: 30 mg. Higher clinical remission vs placebo. Used after failure of prior biologics.",
      color: C.green
    },
    {
      name: "Crohn's Disease",
      trials: "U-EXCEL, U-ENDURE",
      detail: "Clinical remission at Wk 12 induction significantly higher vs placebo. Maintenance with 30 mg sustained remission at 52 weeks.",
      color: "#6A0DAD"
    },
  ];

  diseases.forEach((d, i) => {
    const y = 1.02 + i * 0.9;
    card(s, 0.28, y, 9.44, 0.82, C.white);
    s.addShape(pres.shapes.RECTANGLE, { x: 0.28, y, w: 0.18, h: 0.82, fill: { color: d.color }, line: { color: d.color } });
    s.addText(d.name, { x: 0.58, y: y + 0.04, w: 2.5, h: 0.28, fontSize: 11, bold: true, color: C.navy, fontFace: "Calibri", margin: 0 });
    badge(s, d.trials, 3.15, y + 0.06, 1.7, d.color);
    s.addText(d.detail, { x: 0.58, y: y + 0.36, w: 9.0, h: 0.4, fontSize: 9, color: C.dark, fontFace: "Calibri", margin: 0 });
  });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 9 — DOSING
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  accentBar(s);
  leftStrip(s);
  slideTitle(s, "Dosing & Administration");

  const dosing = [
    { indication: "RA / PsA / AS / nr-AxSpA", dose: "15 mg once daily", notes: "With or without MTX; monotherapy or combination" },
    { indication: "Atopic Dermatitis (≥12 yrs)", dose: "15 mg or 30 mg once daily", notes: "15 mg for adolescents 12–17 yrs; 30 mg option for adults with severe disease" },
    { indication: "Ulcerative Colitis (induction)", dose: "45 mg once daily × 8 weeks", notes: "Then step down to maintenance" },
    { indication: "Ulcerative Colitis (maintenance)", dose: "30 mg once daily", notes: "If adequate response at induction end" },
    { indication: "Crohn's Disease (induction)", dose: "45 mg once daily × 12 weeks", notes: "" },
    { indication: "Crohn's Disease (maintenance)", dose: "30 mg once daily", notes: "FDA approved 2023" },
  ];

  s.addShape(pres.shapes.RECTANGLE, { x: 0.28, y: 0.98, w: 9.44, h: 0.34, fill: { color: C.navy }, line: { color: C.navy } });
  s.addText("Indication", { x: 0.35, y: 0.98, w: 3.5, h: 0.34, fontSize: 10, bold: true, color: C.white, valign: "middle", fontFace: "Calibri", margin: 0 });
  s.addText("Dose", { x: 3.9, y: 0.98, w: 2.5, h: 0.34, fontSize: 10, bold: true, color: C.white, valign: "middle", fontFace: "Calibri", margin: 0 });
  s.addText("Notes", { x: 6.45, y: 0.98, w: 3.1, h: 0.34, fontSize: 10, bold: true, color: C.white, valign: "middle", fontFace: "Calibri", margin: 0 });

  dosing.forEach((row, i) => {
    const y = 1.34 + i * 0.44;
    s.addShape(pres.shapes.RECTANGLE, { x: 0.28, y, w: 9.44, h: 0.42, fill: { color: i % 2 === 0 ? "F4FAFD" : C.white }, line: { color: "D0E8F5", width: 0.5 } });
    s.addText(row.indication, { x: 0.35, y, w: 3.5, h: 0.42, fontSize: 9.5, color: C.dark, bold: true, valign: "middle", fontFace: "Calibri", margin: 0 });
    s.addText(row.dose, { x: 3.9, y, w: 2.5, h: 0.42, fontSize: 9.5, color: C.teal, bold: true, valign: "middle", fontFace: "Calibri", margin: 0 });
    s.addText(row.notes, { x: 6.45, y, w: 3.1, h: 0.42, fontSize: 8.5, color: C.grey, valign: "middle", fontFace: "Calibri", margin: 0 });
  });

  // Administration notes
  card(s, 0.28, 4.05, 9.44, 1.22, "FFF8E8");
  s.addText("⚠  Administration Notes", { x: 0.42, y: 4.1, w: 9.0, h: 0.28, fontSize: 11, bold: true, color: C.amber, fontFace: "Calibri", margin: 0 });
  const adminNotes = [
    "Swallow whole — do NOT crush, split, or chew (extended-release formulation)",
    "Can be taken with or without food",
    "Store at room temperature 20–25°C",
    "Dose reduction may be required with potent CYP3A4 inhibitors (e.g. ketoconazole)",
    "Not recommended in severe hepatic impairment (Child-Pugh C)",
  ];
  adminNotes.forEach((n, i) => {
    s.addText(`• ${n}`, { x: 0.5, y: 4.38 + i * 0.17, w: 9.0, h: 0.16, fontSize: 8.5, color: C.dark, fontFace: "Calibri", margin: 0 });
  });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 10 — SAFETY OVERVIEW
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  accentBar(s);
  leftStrip(s);
  slideTitle(s, "Safety Profile — Overview");

  s.addText("Integrated safety from phase III RA trials (UPA 15 mg; 2630 patients, 4020 pt-yrs)", { x: 0.28, y: 0.9, w: 9.44, h: 0.25, fontSize: 9.5, italic: true, color: C.grey, fontFace: "Calibri", margin: 0 });

  const safetyData = [
    { event: "Upper Respiratory Tract Infection", rate: "Most common AE", severity: "low" },
    { event: "Serious Infections (SIEs)", rate: "3.8 / 100 pt-yrs", severity: "med" },
    { event: "Herpes Zoster", rate: "3.7 / 100 pt-yrs", severity: "med" },
    { event: "Opportunistic Infections", rate: "0.6 / 100 pt-yrs", severity: "high" },
    { event: "Active / Latent TB reactivation", rate: "2.2 / 100 pt-yrs", severity: "high" },
    { event: "Malignancies (excl. NMSC)", rate: "0.9 / 100 pt-yrs", severity: "high" },
    { event: "MACE", rate: "0.6 / 100 pt-yrs", severity: "high" },
    { event: "VTE (DVT/PE)", rate: "0.6 / 100 pt-yrs", severity: "high" },
    { event: "GI Perforations", rate: "0.2 / 100 pt-yrs", severity: "med" },
    { event: "CPK Elevation", rate: "6.1 / 100 pt-yrs (mostly asymp.)", severity: "low" },
    { event: "Hepatic Disorders (LFT rise)", rate: "14.4 / 100 pt-yrs", severity: "med" },
  ];

  const sevColors = { low: C.green, med: C.amber, high: C.red };
  const sevLabel = { low: "Low", med: "Moderate", high: "Monitor" };

  s.addShape(pres.shapes.RECTANGLE, { x: 0.28, y: 1.2, w: 9.44, h: 0.32, fill: { color: C.navy }, line: { color: C.navy } });
  s.addText("Adverse Event", { x: 0.35, y: 1.2, w: 5.0, h: 0.32, fontSize: 9.5, bold: true, color: C.white, valign: "middle", fontFace: "Calibri", margin: 0 });
  s.addText("Rate", { x: 5.4, y: 1.2, w: 2.8, h: 0.32, fontSize: 9.5, bold: true, color: C.white, valign: "middle", fontFace: "Calibri", margin: 0 });
  s.addText("Severity", { x: 8.3, y: 1.2, w: 1.4, h: 0.32, fontSize: 9.5, bold: true, color: C.white, valign: "middle", fontFace: "Calibri", margin: 0 });

  safetyData.forEach((row, i) => {
    const y = 1.54 + i * 0.365;
    s.addShape(pres.shapes.RECTANGLE, { x: 0.28, y, w: 9.44, h: 0.34, fill: { color: i % 2 === 0 ? "F4FAFD" : C.white }, line: { color: "D0E8F5", width: 0.5 } });
    s.addText(row.event, { x: 0.35, y, w: 5.0, h: 0.34, fontSize: 9, color: C.dark, valign: "middle", fontFace: "Calibri", margin: 0 });
    s.addText(row.rate, { x: 5.4, y, w: 2.8, h: 0.34, fontSize: 9, color: C.dark, bold: true, valign: "middle", fontFace: "Calibri", margin: 0 });
    badge(s, sevLabel[row.severity], 8.3, y + 0.05, 1.3, sevColors[row.severity]);
  });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 11 — ORAL SURVEILLANCE
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  accentBar(s, C.red);
  leftStrip(s, C.red);
  slideTitle(s, "ORAL Surveillance Trial & Class Black Box Warning");

  card(s, 0.28, 0.98, 9.44, 1.6, "FFF2F2");
  s.addText("ORAL Surveillance (Tofacitinib) — Why it matters for ALL JAK inhibitors", { x: 0.42, y: 1.04, w: 9.0, h: 0.32, fontSize: 12, bold: true, color: C.red, fontFace: "Calibri", margin: 0 });
  const oralPoints = [
    "FDA-mandated prospective RCT — tofacitinib vs TNF inhibitor (etanercept/adalimumab)",
    "Population: RA patients >50 yrs with ≥1 CV risk factor, on background MTX",
    "Co-primary endpoints: MACE (HR 1.33; 95% CI 0.91–1.94) and Cancer excl. NMSC (HR 1.48; 95% CI 1.04–2.09)",
    "Did NOT meet noninferiority vs TNF inhibitor — FDA extended class warning to ALL JAK inhibitors in 2022",
    "No equivalent safety endpoint trial conducted yet for upadacitinib in this high-risk population",
  ];
  oralPoints.forEach((pt, i) => {
    s.addText(`• ${pt}`, { x: 0.42, y: 1.38 + i * 0.22, w: 9.0, h: 0.2, fontSize: 9, color: C.dark, fontFace: "Calibri", margin: 0 });
  });

  // Black Box Warning box
  card(s, 0.28, 2.65, 9.44, 2.65, "FFF8F8");
  s.addShape(pres.shapes.RECTANGLE, { x: 0.28, y: 2.65, w: 9.44, h: 0.38, fill: { color: C.red }, line: { color: C.red } });
  s.addText("☐  FDA BLACK BOX WARNING — Applies to Upadacitinib (All JAK Inhibitors)", { x: 0.4, y: 2.65, w: 9.1, h: 0.38, fontSize: 11, bold: true, color: C.white, valign: "middle", fontFace: "Calibri", margin: 0 });

  const warnings = [
    ["Serious Infections", "Including TB, bacterial, fungal, viral. Do not initiate during active infection. Screen for TB before starting."],
    ["Malignancy", "Increased risk of malignancies including lymphoma. Risk may be higher in patients with existing CV risk factors/smokers."],
    ["Major Adverse CV Events (MACE)", "Including non-fatal MI, non-fatal stroke, CV death. Higher risk in patients >50 yrs with CV risk factors."],
    ["Thrombosis", "DVT, PE, arterial thrombosis reported. Use with caution in high VTE-risk patients."],
    ["All-cause mortality", "Increased vs TNF inhibitors in ORAL Surveillance (tofacitinib); class effect assumed."],
  ];

  warnings.forEach((w, i) => {
    s.addText(`▸ ${w[0]}: `, { x: 0.42, y: 3.1 + i * 0.42, w: 1.8, h: 0.38, fontSize: 9.5, bold: true, color: C.red, fontFace: "Calibri", valign: "middle", margin: 0 });
    s.addText(w[1], { x: 2.1, y: 3.1 + i * 0.42, w: 7.4, h: 0.38, fontSize: 9, color: C.dark, fontFace: "Calibri", valign: "middle", margin: 0 });
  });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 12 — DRUG INTERACTIONS & SPECIAL POPULATIONS
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  accentBar(s);
  leftStrip(s);
  slideTitle(s, "Drug Interactions & Special Populations");

  // Left col: Drug Interactions
  card(s, 0.28, 0.98, 4.6, 4.3, C.white);
  s.addText("Drug Interactions", { x: 0.4, y: 1.04, w: 4.3, h: 0.3, fontSize: 13, bold: true, color: C.navy, fontFace: "Calibri", margin: 0 });

  const ddi = [
    ["Strong CYP3A4 inhibitors", "Ketoconazole, clarithromycin", "Reduce UPA dose (15 mg→ not recommended at higher dose)", C.red],
    ["Strong CYP3A4 inducers", "Rifampin, phenytoin", "Decreased UPA exposure — avoid combination", C.red],
    ["Live vaccines", "All live attenuated", "Contraindicated during therapy", C.red],
    ["Immunosuppressants", "Azathioprine, cyclosporine", "Avoid — increased immunosuppression risk", C.amber],
    ["Methotrexate (low dose)", "Background csDMARD", "Generally safe; used in RA combo regimens", C.green],
  ];

  ddi.forEach((row, i) => {
    const y = 1.4 + i * 0.72;
    s.addShape(pres.shapes.ROUNDED_RECTANGLE, { x: 0.38, y, w: 4.3, h: 0.65, fill: { color: i % 2 === 0 ? "F4FAFD" : C.white }, line: { color: "D0E8F5", width: 0.5 }, rectRadius: 0.05 });
    s.addText(row[0], { x: 0.48, y: y + 0.02, w: 3.6, h: 0.22, fontSize: 9.5, bold: true, color: row[3], fontFace: "Calibri", margin: 0 });
    s.addText(row[1], { x: 0.48, y: y + 0.22, w: 3.6, h: 0.2, fontSize: 8.5, color: C.grey, italic: true, fontFace: "Calibri", margin: 0 });
    s.addText(row[2], { x: 0.48, y: y + 0.4, w: 3.6, h: 0.2, fontSize: 8.5, color: C.dark, fontFace: "Calibri", margin: 0 });
  });

  // Right col: Special populations
  card(s, 5.1, 0.98, 4.62, 4.3, C.white);
  s.addText("Special Populations", { x: 5.22, y: 1.04, w: 4.3, h: 0.3, fontSize: 13, bold: true, color: C.navy, fontFace: "Calibri", margin: 0 });

  const popData = [
    ["Pregnancy", C.red, "Contraindicated — teratogenic in animal studies. Effective contraception required during & 4 wks after last dose."],
    ["Lactation", C.red, "Avoid — unknown if excreted in breast milk."],
    ["Paediatric (<12 yrs)", C.amber, "Not approved. AD indication from age 12."],
    ["Renal Impairment", C.amber, "Mild/moderate: no dose adjustment. Severe (eGFR <15): limited data — use with caution."],
    ["Hepatic Impairment", C.amber, "Mild/moderate: no adjustment. Severe (Child-Pugh C): not recommended."],
    ["Elderly (>65 yrs)", C.amber, "Use with caution — higher risk of serious infections, MACE, and cancer in this group."],
  ];

  popData.forEach((p, i) => {
    const y = 1.42 + i * 0.62;
    s.addShape(pres.shapes.ROUNDED_RECTANGLE, { x: 5.18, y, w: 4.42, h: 0.55, fill: { color: i % 2 === 0 ? "F4FAFD" : C.white }, line: { color: "D0E8F5", width: 0.5 }, rectRadius: 0.05 });
    s.addShape(pres.shapes.ROUNDED_RECTANGLE, { x: 5.22, y: y + 0.06, w: 0.65, h: 0.22, fill: { color: p[1] }, line: { color: p[1] }, rectRadius: 0.04 });
    s.addText(p[0], { x: 5.22, y: y + 0.06, w: 0.65, h: 0.22, fontSize: 8, bold: true, color: C.white, align: "center", valign: "middle", fontFace: "Calibri", margin: 0 });
    s.addText(p[2], { x: 5.95, y: y + 0.04, w: 3.55, h: 0.46, fontSize: 8.5, color: C.dark, fontFace: "Calibri", valign: "middle", margin: 0 });
  });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 13 — UPA vs TOFACITINIB
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  accentBar(s);
  leftStrip(s);
  slideTitle(s, "Upadacitinib vs Tofacitinib — Head-to-Head Comparison");

  const compData = [
    ["Feature", "Upadacitinib", "Tofacitinib"],
    ["JAK Selectivity", "Highly selective JAK1 (>70x over JAK2)", "JAK1 + JAK3 (less selective)"],
    ["Dosing", "15 mg once daily", "5 mg BID or 11 mg XR once daily"],
    ["Efficacy vs adalimumab", "Statistically superior in SELECT-COMPARE", "Non-inferior in head-to-head"],
    ["Efficacy vs abatacept", "Superior (SELECT-CHOICE)", "Not directly compared"],
    ["Atopic Dermatitis", "Approved (15/30 mg)", "Not approved"],
    ["Crohn's Disease", "Approved (2023)", "Not approved"],
    ["JIA", "Not approved", "Approved (polyarticular JIA)"],
    ["MACE/Cancer data", "Class warning; no dedicated safety trial", "ORAL Surveillance: HR 1.33 MACE, 1.48 cancer"],
    ["Anemia risk", "Lower (JAK2 spared)", "Higher (JAK2 off-target)"],
    ["CPK elevation", "More common (6.1/100 pt-yrs)", "Less prominent"],
    ["Hepatotoxicity", "More common (LFT elevation)", "Less prominent"],
    ["Drug interactions", "CYP3A4", "CYP2C19 + CYP3A4"],
    ["Generic available?", "No (patent-protected)", "Yes (increasingly available)"],
  ];

  compData.forEach((row, i) => {
    const y = 0.98 + i * 0.33;
    const isHeader = i === 0;
    s.addShape(pres.shapes.RECTANGLE, { x: 0.28, y, w: 9.44, h: 0.31, fill: { color: isHeader ? C.navy : i % 2 === 0 ? "EBF5FB" : C.white }, line: { color: "D0E8F5", width: 0.5 } });
    const fc = isHeader ? C.white : C.dark;
    const bc = isHeader ? C.white : C.teal;
    s.addText(row[0], { x: 0.35, y, w: 2.5, h: 0.31, fontSize: isHeader ? 9.5 : 9, bold: isHeader, color: bc, valign: "middle", fontFace: "Calibri", margin: 0 });
    s.addText(row[1], { x: 2.9, y, w: 3.4, h: 0.31, fontSize: 9, bold: false, color: fc, valign: "middle", fontFace: "Calibri", margin: 0 });
    s.addText(row[2], { x: 6.35, y, w: 3.3, h: 0.31, fontSize: 9, bold: false, color: fc, valign: "middle", fontFace: "Calibri", margin: 0 });
  });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 14 — UPA vs BIOLOGICS
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  accentBar(s);
  leftStrip(s);
  slideTitle(s, "Upadacitinib vs Biologics in RA");

  const bioComp = [
    ["Feature", "Upadacitinib (JAKi)", "TNF Inhibitors", "IL-6 Inhibitors (TCZ/SAR)", "Abatacept"],
    ["Route", "Oral", "SC/IV", "SC/IV", "SC/IV"],
    ["Onset of action", "Rapid (1–2 wks)", "2–4 weeks", "2–4 weeks", "Slower (4–8 wks)"],
    ["Efficacy vs MTX-IR", "Superior to adalimumab", "Superior (standard of care)", "Superior", "Superior"],
    ["Head-to-head vs bDMARD", "Superior to abatacept; superior to adalimumab (SELECT-COMPARE)", "Gold standard comparator", "Noninferior to adalimumab", "Comparator in SELECT-CHOICE"],
    ["Infection risk", "Elevated (class)", "Elevated", "Elevated", "Lower than others"],
    ["CV/Cancer risk", "Class warning", "Lower vs JAKi in OS trial", "Neutral CV", "Lowest CV risk"],
    ["Immunogenicity", "None (small molecule)", "High (ADA formation)", "Moderate", "Low"],
    ["Pregnancy", "Contraindicated", "Generally avoid", "Avoid", "Limited data"],
    ["Cost", "High (no generic)", "High (some biosimilars)", "High", "High"],
  ];

  bioComp.forEach((row, i) => {
    const y = 0.98 + i * 0.44;
    const isHeader = i === 0;
    s.addShape(pres.shapes.RECTANGLE, { x: 0.28, y, w: 9.44, h: 0.42, fill: { color: isHeader ? C.navy : i % 2 === 0 ? "EBF5FB" : C.white }, line: { color: "D0E8F5", width: 0.5 } });
    const fc = isHeader ? C.white : C.dark;
    [row[0], row[1], row[2], row[3], row[4]].forEach((cell, j) => {
      const xPos = [0.3, 1.95, 3.68, 5.55, 7.42];
      const wArr = [1.55, 1.7, 1.8, 1.82, 2.2];
      s.addText(cell, { x: xPos[j], y, w: wArr[j], h: 0.42, fontSize: isHeader ? 8.5 : 8, bold: isHeader, color: isHeader ? C.white : j === 1 ? C.teal : fc, valign: "middle", fontFace: "Calibri", margin: 2 });
    });
  });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 15 — PATIENT SELECTION
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  accentBar(s);
  leftStrip(s);
  slideTitle(s, "Patient Selection — Who is an Ideal Candidate?");

  // Good candidates
  card(s, 0.28, 0.98, 4.5, 4.3, C.white);
  s.addShape(pres.shapes.RECTANGLE, { x: 0.28, y: 0.98, w: 4.5, h: 0.38, fill: { color: C.green }, line: { color: C.green } });
  s.addText("✓  Suitable Candidates", { x: 0.38, y: 0.98, w: 4.2, h: 0.38, fontSize: 12, bold: true, color: C.white, valign: "middle", fontFace: "Calibri", margin: 0 });

  const good = [
    "Moderate-to-severe RA with inadequate response to csDMARDs (especially MTX)",
    "bDMARD-experienced patients needing step-up therapy",
    "Patients who prefer oral therapy over injections",
    "Active PsA, AS, nr-AxSpA with inadequate NSAID/bDMARD response",
    "Moderate-to-severe atopic dermatitis (refractory to topicals/dupilumab)",
    "UC/Crohn's refractory to anti-TNF or vedolizumab",
    "Patients where rapid onset of action is desired",
    "Those without high CV risk factors or active malignancy",
  ];
  good.forEach((g, i) => {
    s.addText(`✓ ${g}`, { x: 0.38, y: 1.43 + i * 0.44, w: 4.22, h: 0.4, fontSize: 9, color: C.dark, fontFace: "Calibri", valign: "top", margin: 0 });
  });

  // Poor candidates
  card(s, 5.0, 0.98, 4.72, 4.3, C.white);
  s.addShape(pres.shapes.RECTANGLE, { x: 5.0, y: 0.98, w: 4.72, h: 0.38, fill: { color: C.red }, line: { color: C.red } });
  s.addText("✗  Use with Caution / Avoid", { x: 5.12, y: 0.98, w: 4.4, h: 0.38, fontSize: 12, bold: true, color: C.white, valign: "middle", fontFace: "Calibri", margin: 0 });

  const bad = [
    "Active serious infections (TB, fungal, bacterial sepsis)",
    "Age >50 with multiple CV risk factors — increased MACE risk",
    "Prior or current malignancy (especially lymphoma, lung cancer)",
    "Severe hepatic impairment (Child-Pugh C)",
    "Pregnancy or planned pregnancy",
    "Active or recent thrombosis (DVT/PE)",
    "Combination with potent immunosuppressants (azathioprine, CsA)",
    "Patients who have not trialled csDMARDs first (in RA)",
  ];
  bad.forEach((b, i) => {
    s.addText(`✗ ${b}`, { x: 5.1, y: 1.43 + i * 0.44, w: 4.52, h: 0.4, fontSize: 9, color: C.dark, fontFace: "Calibri", valign: "top", margin: 0 });
  });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 16 — MONITORING
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  accentBar(s);
  leftStrip(s);
  slideTitle(s, "Monitoring & Follow-up");

  const monData = [
    { timing: "Before initiation", items: ["Screen for active/latent TB (IGRA or TST + CXR)", "Screen for viral hepatitis (HBV, HCV serology)", "Full blood count (FBC): rule out lymphopenia, neutropenia, anaemia", "Lipid panel (baseline)", "Liver function tests (LFTs)", "Renal function (eGFR)", "Assess CV risk factors / malignancy history", "Update vaccinations (incl. herpes zoster vaccine — ideally before starting)"], color: C.midTeal },
    { timing: "4–8 weeks after start", items: ["FBC — monitor for cytopenias", "LFTs — watch for hepatic transaminase elevation", "Lipid panel — JAK inhibitors can raise LDL/HDL", "CPK if myalgia reported", "Clinical response assessment (DAS28/CDAI)"], color: C.teal },
    { timing: "Every 3 months", items: ["FBC, LFTs, lipids", "Disease activity scoring", "Assess for infections, zoster", "Monitor BP and CV risk", "Watch for skin changes / new malignancy"], color: C.amber },
    { timing: "Every 6–12 months", items: ["Annual malignancy screen (skin, lymph nodes)", "Annual TB risk re-assessment", "Annual lipid panel + CV risk calculation", "Radiological assessment of disease in RA/AxSpA as needed"], color: C.green },
  ];

  monData.forEach((m, i) => {
    const y = 0.98 + i * 1.15;
    card(s, 0.28, y, 9.44, 1.08, C.white);
    s.addShape(pres.shapes.RECTANGLE, { x: 0.28, y, w: 1.8, h: 1.08, fill: { color: m.color }, line: { color: m.color } });
    s.addText(m.timing, { x: 0.28, y, w: 1.8, h: 1.08, fontSize: 10, bold: true, color: C.white, align: "center", valign: "middle", fontFace: "Calibri", margin: 4 });
    const perRow = Math.ceil(m.items.length / 2);
    m.items.forEach((item, j) => {
      const col = Math.floor(j / perRow);
      const row = j % perRow;
      s.addText(`• ${item}`, { x: 2.22 + col * 3.7, y: y + 0.1 + row * 0.2, w: 3.5, h: 0.18, fontSize: 8, color: C.dark, fontFace: "Calibri", margin: 0 });
    });
  });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 17 — KEY TRIALS SUMMARY
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  accentBar(s);
  leftStrip(s);
  slideTitle(s, "Key Clinical Trials Summary");

  const trials = [
    { name: "SELECT-COMPARE", n: "1629", disease: "RA", pop: "MTX-IR", comparator: "Adalimumab", key: "UPA superior to ADA; ACR50 45% vs 29%", color: C.teal },
    { name: "SELECT-MONOTHERAPY", n: "648", disease: "RA", pop: "MTX-IR", comparator: "Placebo + MTX continue", key: "UPA monotherapy superior to MTX", color: C.midTeal },
    { name: "SELECT-NEXT", n: "661", disease: "RA", pop: "csDMARD-IR", comparator: "Placebo", key: "ACR20 at Wk12: 64% vs 36%", color: C.navy },
    { name: "SELECT-BEYOND", n: "498", disease: "RA", pop: "bDMARD-IR", comparator: "Placebo", key: "Effective after biologic failure", color: "#1565C0" },
    { name: "SELECT-EARLY", n: "945", disease: "RA", pop: "MTX-naive", comparator: "MTX", key: "Higher ACR50; less X-ray progression", color: C.green },
    { name: "SELECT-CHOICE", n: "612", disease: "RA", pop: "bDMARD-IR", comparator: "Abatacept", key: "UPA superior in remission; more AEs", color: C.amber },
    { name: "SELECT-PsA 1 & 2", n: "1704 + 642", disease: "PsA", pop: "biologic-naive / TNFi-IR", comparator: "Adalimumab / Placebo", key: "Noninferior to ADA; superior to PBO", color: C.teal },
    { name: "SELECT-AXIS 1 & 2", n: "187 + 420", disease: "AS/nr-AxSpA", pop: "bDMARD-naive / TNFi-IR", comparator: "Placebo", key: "ASAS40 significantly higher at Wk14", color: C.midTeal },
    { name: "Measure Up 1 & 2", n: "1609", disease: "Atopic Derm.", pop: "Adults/adolescents", comparator: "Placebo", key: "EASI-75 at Wk16: ~65–70%", color: C.amber },
    { name: "U-ACHIEVE / U-ACCOMPLISH", n: "691 + 788", disease: "UC", pop: "Biologic-IR/naive", comparator: "Placebo", key: "Higher clinical remission at Wk8", color: C.green },
  ];

  s.addShape(pres.shapes.RECTANGLE, { x: 0.28, y: 0.98, w: 9.44, h: 0.3, fill: { color: C.navy }, line: { color: C.navy } });
  ["Trial", "N", "Disease", "Key Finding"].forEach((h, j) => {
    const xs = [0.35, 2.0, 2.7, 4.5];
    const ws = [1.6, 0.65, 1.7, 5.3];
    s.addText(h, { x: xs[j], y: 0.98, w: ws[j], h: 0.3, fontSize: 9, bold: true, color: C.white, valign: "middle", fontFace: "Calibri", margin: 0 });
  });

  trials.forEach((t, i) => {
    const y = 1.3 + i * 0.43;
    s.addShape(pres.shapes.RECTANGLE, { x: 0.28, y, w: 9.44, h: 0.41, fill: { color: i % 2 === 0 ? "EBF5FB" : C.white }, line: { color: "D0E8F5", width: 0.5 } });
    s.addShape(pres.shapes.ROUNDED_RECTANGLE, { x: 0.32, y: y + 0.06, w: 1.6, h: 0.28, fill: { color: t.color }, line: { color: t.color }, rectRadius: 0.04 });
    s.addText(t.name, { x: 0.32, y: y + 0.06, w: 1.6, h: 0.28, fontSize: 8, bold: true, color: C.white, align: "center", valign: "middle", fontFace: "Calibri", margin: 0 });
    s.addText(t.n, { x: 2.0, y, w: 0.65, h: 0.41, fontSize: 8.5, color: C.dark, valign: "middle", fontFace: "Calibri", margin: 0 });
    s.addText(t.disease, { x: 2.7, y, w: 1.7, h: 0.41, fontSize: 8.5, color: C.dark, bold: true, valign: "middle", fontFace: "Calibri", margin: 0 });
    s.addText(t.key, { x: 4.5, y, w: 5.1, h: 0.41, fontSize: 8.5, color: C.dark, valign: "middle", fontFace: "Calibri", margin: 0 });
  });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 18 — CLINICAL PEARLS
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  accentBar(s, C.green);
  leftStrip(s, C.green);
  slideTitle(s, "Clinical Pearls");

  const pearls = [
    { icon: "💊", title: "Selectivity ≠ safety", detail: "JAK1 selectivity reduces hematologic off-targets but does NOT eliminate CV/cancer risk. All JAKi carry the same class black box warning." },
    { icon: "⚡", title: "Rapid Onset", detail: "Patients often report improvement in pain and stiffness within 1–2 weeks — faster than most biologics. Useful when quick disease control is needed." },
    { icon: "🎯", title: "Efficacy Advantage", detail: "One of very few DMARDs to demonstrate superiority (not just non-inferiority) vs adalimumab in MTX-IR RA — a clinically meaningful benchmark." },
    { icon: "⚠️", title: "Herpes Zoster Risk", detail: "Zoster rates (~3.7/100 pt-yrs) are notably higher than with biologics. Offer recombinant zoster vaccine (Shingrix) before starting if possible." },
    { icon: "🩸", title: "CPK & LFT Monitoring", detail: "Asymptomatic CPK elevation is common; monitor and investigate if symptomatic. LFT elevations at 14.4/100 pt-yrs — check LFTs at baseline and regularly." },
    { icon: "🧬", title: "IBD Advantage", detail: "Upadacitinib is the only JAK inhibitor with FDA approval for both UC and Crohn's disease at 30 mg maintenance — offering an oral option post-biologic failure." },
    { icon: "👶", title: "Women of childbearing age", detail: "Mandatory contraception. If pregnancy is desired, plan washout period (at least 4 weeks before conception attempt)." },
    { icon: "🔁", title: "Switching from biologics", detail: "No washout required when switching from most biologics (except for live vaccines and combination immunosuppressants — check each case)." },
  ];

  pearls.forEach((p, i) => {
    const col = i % 2;
    const row = Math.floor(i / 2);
    const x = 0.28 + col * 4.85;
    const y = 1.02 + row * 1.12;
    card(s, x, y, 4.65, 1.02, C.white);
    s.addText(p.icon, { x: x + 0.1, y: y + 0.08, w: 0.6, h: 0.55, fontSize: 20, align: "center", valign: "middle", fontFace: "Calibri", margin: 0 });
    s.addText(p.title, { x: x + 0.75, y: y + 0.08, w: 3.75, h: 0.28, fontSize: 10.5, bold: true, color: C.navy, fontFace: "Calibri", margin: 0 });
    s.addText(p.detail, { x: x + 0.75, y: y + 0.36, w: 3.75, h: 0.58, fontSize: 8.5, color: C.dark, fontFace: "Calibri", margin: 0 });
  });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 19 — REFERENCES & CLOSING
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  darkBg(s);
  s.addShape(pres.shapes.RECTANGLE, { x: 6.2, y: 0, w: 3.8, h: 5.625, fill: { color: C.midTeal }, line: { color: C.midTeal } });
  s.addShape(pres.shapes.RECTANGLE, { x: 5.9, y: 0, w: 0.35, h: 5.625, fill: { color: C.teal }, line: { color: C.teal } });

  s.addText("Key References", { x: 0.4, y: 0.4, w: 5.2, h: 0.5, fontSize: 22, bold: true, color: C.white, fontFace: "Calibri", margin: 0 });

  const refs = [
    "Firestein & Kelley's Textbook of Rheumatology, 2-Volume Set (2024, Elsevier) — JAK Inhibitor chapters",
    "Rheumatology, 2-Volume Set (2022, Elsevier) — Chapters on tsDMARDs and upadacitinib",
    "Lippincott Illustrated Reviews: Pharmacology — JAK-STAT pathway and tofacitinib",
    "Genovese MC et al. SELECT-COMPARE: N Engl J Med 2019",
    "Smolen JS et al. SELECT-MONOTHERAPY: Lancet 2019",
    "Fleischmann R et al. SELECT-EARLY: Arthritis Rheumatol 2019",
    "Burmester GR et al. SELECT-BEYOND: Ann Rheum Dis 2018",
    "Rubbert-Roth A et al. SELECT-CHOICE: Ann Rheum Dis 2021",
    "McInnes IB et al. SELECT-PsA 1: Lancet 2021",
    "Mease PJ et al. SELECT-PsA 2: Lancet 2021",
    "FDA Safety Communication: JAK inhibitor class warnings (2022)",
    "ORAL Surveillance Trial: Ytterberg SR et al. N Engl J Med 2022",
    "Thomas J et al. Cochrane NMA on DMARDs after biologic failure (Jul 2026, PMID 42440279)",
  ];

  refs.forEach((r, i) => {
    s.addText(`${i + 1}. ${r}`, { x: 0.4, y: 0.98 + i * 0.34, w: 5.3, h: 0.32, fontSize: 8.5, color: "A8D8EA", fontFace: "Calibri", margin: 0 });
  });

  // Right panel closing
  s.addText([
    { text: "Upadacitinib\n", options: { bold: true, breakLine: true, fontSize: 22 } },
    { text: "Selective JAK1 Inhibitor\n", options: { breakLine: true, fontSize: 13, color: "D6EEF8" } },
    { text: "\nA clinically significant advance\nin oral targeted therapy\nfor inflammatory diseases.", options: { fontSize: 11, color: "A8D8EA" } }
  ], { x: 6.25, y: 1.6, w: 3.4, h: 2.5, fontFace: "Calibri", color: C.white, align: "center", valign: "middle" });

  s.addText("Thank you", { x: 6.25, y: 4.1, w: 3.4, h: 0.5, fontSize: 16, bold: true, color: C.teal, align: "center", fontFace: "Calibri", margin: 0 });
  s.addText("Prepared by Orris AI  |  July 2026", { x: 0.4, y: 5.2, w: 5.0, h: 0.28, fontSize: 8, color: "4D7A9E", fontFace: "Calibri", margin: 0 });
}

// ═══════════════════════════════════════════════════════════
// WRITE FILE
// ═══════════════════════════════════════════════════════════
pres.writeFile({ fileName: "/home/daytona/workspace/upadacitinib-pptx/Upadacitinib_Clinical_Review.pptx" })
  .then(() => console.log("SUCCESS: File saved."))
  .catch(e => { console.error("ERROR:", e); process.exit(1); });